Factors that influence the therapeutic activity of 5-fluorouracil [6RS]leucovorin combinations in colon adenocarcinoma xenografts

The therapeutic activity of FUra alone or combined with [6RS]LV doses ranging from 50 to 1,000 mg/m² was examined in eight colon adenocarcinoma xenografts, of which five were established from adult neoplasms (HxELC₂, HxGC₃, HxVRC₅, HxHC₁, and HxGC₃/c1TK-c3 selected for TK deficiency) and three were derived from adolescent tumors (HxSJC₃A, HxSJC₃B, and HxSJC₂). The growth-inhibitory effects of FUra were potentiated by higher doses of [6RS]LV (500-1,000 mg/m²) in three lines (HxGC₃/c1TK-c3, HxSJC₃A, and HxSJC₃B) and by a low dose of [6RS]LV in only one tumor (HxVRC₅). Expansion of pools of CH₂-H₄PteGlu_n+H₄PteGlu_n (≥2.4-fold) in response to higher doses of [6RS]LV was obtained in all lines except HxHC₁. Metabolism of [6RS]LV was high in HxVRC₅, with high levels of 5-CH₃-H₄PteGlu being detected, but not in HxHC₁, in which levels of 5-CH₃-H₄PteGlu and CH=H₄PteGlu+10-CHO-H₄PteGlu remained relatively low. In the adolescent tumors, levels of CH=H₄PteGlu+10-CHO-H₄PteGlu those of 5-CH₃-H₄PteGlu following [6RS]LV administration. and in HxSJC₃A, in which pools of CH₂-H₄Pte-Glu_n+H₄PteGlu_n were significantly expanded, 5-CH₃-H₄PteGlu concentrations were lower than those observed in the other two lines. The sensitivity of tumors to FUra±[6RS]LV and the characteristics of [6S]LV metabolism did not correlate with the activity of CH=H₄PteGlu synthetase, the enzyme responsible for the initial cellular metabolism of [6S]LV to CH=H₄PteGlu. Thus, no single metabolic phenotype correlated with the [6RS]LV-induced expansion of CH₂-H₄PteGlu_n+H₄PteGlu_n pools. Potentiation of the therapeutic efficacy of FUra by [6RS]LV was observed in HxGC₃c1TK-c3 xenografts but not in parent HxGC₃ tumors, demonstrating the influence of dThd salvage capability in the response to FUra-[6RS]LV combinations. Plasma dThd concentrations in CBA/CaJ mice were high (1.1 μm). The present data therefore demonstrate the importance of (1) higher doses of [6RS]LV, (2) expansion of pools of CH₂-H₄PteGlu_n+H₄PteGlu_n, and (3) dThd salvage capability in potentiation of the therapeutic efficacy of FUra in colon adenocarcinoma xenogafts. The plasma levels of FUra achieved in mice are presented.